It is known that in cells of vertebrate animals protection against damage by virus infections can be obtained by means of a contact between viruses and certain other microbial substances. It is assumed that this contact induces the formation of materials which hinder the viruses that have penetrated the cell in their replication. The biochemical mechanism of the antiviral activity is still under discussion. The induced antiviral proteins--for example, the interferon--are specific to virus species.
Therefore, it is of great significance to find suitable inducers which cause directly in the human organism the formation of these inhibiting proteins, which are then at the disposal for general defense against viruses.
A survey of the activity of substances tested for their interferon-inducing action according to prior art is given in Table I (R. F. Beers and W. Braun "Biological Effects of Polynucleotides"; published by Springer Verlag Stuttgart, Germany, 1971).
Table I ______________________________________ i.v. dose Interferon- per titre Polynucleotide rabbit (.mu.g) (rabbit) ______________________________________ Poly I:C 2 640 Poly A:U 25 20 RNA from Reovirus 3 8 640 RNA from M S 2 Coliphagen 8 160 RNA from M U 9 Coliphagen-Mutants 2 40 RNA from Escherichia coli 100 0 RNA from Influenza virus 10 0 Total RNA yeast 100 0 t-RNA from yeast 200 0 RNA from yeast ribosomes 1000 0 t-RNA from bovine liver 200 0 ______________________________________
As the table by way of the example for the interferon titre shows, the intensity of the inducing activity differs greatly; the partially synthetically obtained Poly I:C is very effective, for example, while the transfer-ribonucleinic acids (t-RNA) do not show any effect here.
As a measure of the activity of an inducing substance, the antiviral effectiveness is employed. It is determined in vitro as the inhibition of the infective activity of a virus in a cell culture, where the number of the plaques that are formed in the cell-lysis caused by infection is determined. [Finter, N. V.: Interferon Assays and Standards; in "Interferons" (North-Holland Publ. Company, Amsterdam, Holland, 1966).--Lorenz, R. J.: Zur Statistik des Plaque--Testes, Arch. Ges. Virusforsch. 12, 108-137 (1963)].
In the in vivo test a number of animals are infected by a virus in a specific range of the lethal dose, and the increase of the rate of surviving animals or the decrease of the symptoms of the disease or the number of the virus genes in the blood (viremia) is determined by means of the inducing substance.
Due to its high effectiveness, Poly I:C was generally found to be of theoretical and practical interest. For example, it has been used against local keratitis in the eye; but a systemic use in human organisms is prevented by its toxicity, which is comparable to that of endotoxin [see M. Absher and W. Stineberg, Nature 223, page 715 (1969), as well as H. L. Lindsay, P. W. Trown and J. Brandt, Nature 223, page 717 (1969)].